(a) Field of the Invention
The present invention relates to a method of regulating mammalian target-of-rapamycin (mTOR) by regulating a phospholipase D (PLD) activity that generates a complex with mTOR. Further, the present invention also relates to a method of screening inhibitors of mTOR, and a method and a composition for treating mTOR-related metabolic diseases by inhibiting mTOR.
(b) Description of the Related Art
mTOR is a serine/threonine protein kinase and a member of a novel superfamily of signaling proteins termed PI 3-kinase related kinases (PIKKs), based on sequence similarity of their catalytic domains. The mTOR pathway is an emerging target for the treatment of cancer, diabetes and obesity. Further, recent studies have demonstrated the mTOR's role as a mediator of lifespan control in C. elegans and Drosophila. However, despite the significance of this pathway in such diverse biological processes, the mechanism of its regulation by upstream signals remains to be addressed.
In addition, mTOR requires the lipid second messenger phosphatidic acid (PA) for its activation. PA is an enzymatic product of PLD. PLD, which hydrolyzes phosphatidylcholine (PC) to generate PA, constitutes another branch of the mTOR upstream regulators through which mitogenic signals impinge on the mTOR pathway. Mammalian PLD isozymes identified to date, PLD1 and PLD2, sense a variety of signals, such as neurotransmitters, hormones and growth factors, to regulate multiple physiological events such as proliferation, secretion, respiratory burst and actin cytoskeletal reorganization, and the like.
Here, the present inventors have studied regarding the regulatory mechanisms of mTOR signaling and found that the physical/functional connections between mitogen-induced PA generation and its effector, mTOR, to complete the present invention (see FIG. 21).